Oxymatrine (OMT), a water-soluble drug, has a very low oral bioavailability because of its low membrane permeability and its biotransformation in the gastrointestinal tract. Formulated as an oxymatrine-phospholipid complex (OMT-PLC) can improve the lipid solubility and effectiveness of OMT. The purpose of this study was to explore the utility of the combination of a microemulsion and an OMT-PLC as a topical delivery vehicle for enhancing the absorption and efficacy of OMT. The solubility of OMT-PLC was determined and phase diagrams of microemulsions were constructed. Various microemulsion formulations were developed and characterized by their physicochemical properties, and their in vitro and in vivo permeability through skin. An optimal microemulsion (ME4), which presented as spherical droplets and consisted of 10.0% OMT-PLC, 8.0% isopropyl myristate, 30.0% Cremophor RH40/polyethylene glycol 400 (1:1) and 52.0% water, was selected. It possessed an average droplet size of 32.4 nm, a low viscosity of 113.7 mPa · s, and a high cloud point of 88°C. Compared to the control solution, ME4 provided better skin permeability in vitro and a higher retention ratio of OMT in skin in vivo. Moreover, ME4 significantly enhanced the antiproliferative activity of OMT on scar fibroblasts. These results indicate that the combination of a microemulsion and a phospholipid complex represents an effective vehicle for topical delivery of OMT.